Survival outcomes in ALK-positive NSCLC patients (p) treated 1<sup>st</sup> line brigatinib and impact of the ALK fusion variant.
Authors: Mariano Provencio-Pulla, Rosario Garcia Campelo, Aitor Azkarate, Virginia Calvo, Manuel Cobo, Joaquín Mosquera, Ernest Nadal, Delvys Rodriguez-Abreu, Raquel Marse Fabregat, Ana Callejo, Manuel Domine, Oscar Juan-Vidal, Francisco Garcia-Garcia, Estela Sanchez, Atocha Romero
Journal: Journal of Clinical Oncology (2023)

e21015 Background: There is limited data on brigatinib (a next-generation anaplastic lymphoma kinase (ALK) inhibitor) efficacy according to the ALK fusion variant. Here we investigate the prevalence of ALK fusion variants and evaluate treatment outcomes in ALK-positive NSCLC treated with first-line brigatinib. Methods: This is an open-label, non-randomized, phase II, exploratory, multi-center clinical trial. Stage IV, ALK-positive NSCLC p were treated with brigatinib 90mg for the first 7 days (D 1-7 at cycle 1) and then 180 mg daily thereafter for QW4 cycles of duration (28 days ±3days). Brigatinib was administered until loss of clinical benefit, unacceptable toxicity, p or physician decision to discontinue, or death. Response to treatment was evaluated as per RECIST v1.1. ALK rearrangement was identified locally by immunohistochemistry and confirmed by fluorescence in situ hybridization. In addition, baseline tissue samples were analyzed by NGS using the Oncomine™ Focus Assay in a centralized laboratory. Results: Between May 2020 and October 2021, 33 p were enrolled from eight different institutions. One p was considered not valid because there no tissue or plasma sample was available at baseline. Therefore, 32 p were finally considered for the study. Baseline characteristics were as follows: median age (range): 53 (35-86) years; female, n = 15 (47%); ECOG PS of 0 n = 6 (19%), 1 n = 23 (72%), 2 n = 3 (9%); never smoker, n = 14 (44%). All tumors were adenocarcinoma. The average number of metastases per p was four. In total, seven (22%) p had brain metastases. A sample was valid for NGS analysis in 29 cases. ALK fusion partners were EML4 in 28 cases (97%) and HIP1 in one case (3%). The ALK fusion variant 1 was the most frequently detected (n = 13, 45%), followed by variant 3 (n = 9; 31%), and variant 2 (n = 4; 14%). The EML4(6)-ALK(19) variant was detected in 2 cases, and variant 8 was detected in one case. The median follow-up time was 18 months. During the study, 13 deaths were recorded, and progressive disease (PD) was observed in 15 p. With a data maturity of 87%, median progression-free survival (PFS) was 16.7 months (95%CI 6.2-NR), and median overall survival (OS) was NR (95%CI 12.4-NR). There were no significant differences in survival outcomes according to the type of variant. The same was true when grouping long (variants 1,2 and 8) and short (variant 3, EML4(6) - ALK(19)) variants. The p whose tumor harbored the HIP1(21)-ALK(20) variant was alive and with and in partial response at the time of data cutoff. On the other hand, a patient whose tumor harbored the short variant EML4(6) - ALK(19) along with the KRAS G12C mutation was diagnosed with disease progression after three months of treatment initiation and deceased after eight months from the start of treatment. Conclusions: In this interim analysis we were unable to demonstrate a significant difference in survival outcomes according to variant type. Clinical trial information: NCT04223596 .